Pancreatic cancer molecular classifications: From bulk genomics to single cell analysis

Pancreatic cancer represents one of the most lethal disease worldwide but still orphan of a molecularly driven therapeutic approach, although many genomic and transcriptomic classifications have been proposed over the years. Clinical heterogeneity is a hallmark of this disease, as different patients show different responses to the same therapeutic regimens. However, genomic analyses revealed quite a homogeneous disease picture, with very common mutations in four genes only (KRAS, TP53, CDKN2A, and SMAD4) and a long tail of other mutated genes, with doubtful pathogenic meaning. Even bulk transcriptomic classifications could not resolve this great heterogeneity, as many informations related to small cell populations within cancer tissue could be lost. At the same time, single cell analysis has emerged as a powerful tool to dissect intratumoral heterogeneity like never before, with possibility of generating a new disease taxonomy at unprecedented molecular resolution. In this review, we summarize the most relevant genomic, bulk and single-cell transcriptomic classifications of pancreatic cancer, and try to understand how novel technologies, like single cell analysis, could lead to novel therapeutic strategies for this highly lethal disease

Early triple negative breast cancer: Conventional treatment and emerging therapeutic landscapes

Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline-and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches have been evaluated to improve survival outcomes. The addition of platinum salts to standard neoadjuvant chemotherapy (NACT) remains controversial due to the lack of clear survival advantage, and the use of adjuvant capecitabine represents a valid treatment option in TNBC patients with residual disease after NACT. Recently, several clinical trials showed promising results through the use of poly ADP-ribose polymerase (PARP) inhibitors and by incorporating immunotherapy with chemotherapy, enriching treatment options beyond conventional cytotoxic agents. In this review, we provided an overview on the current standard of care and a comprehensive update of the recent advances in the management of early stage TNBC and focused on the latest emerging biomarkers and their clinical application to select the best therapeutic strategy in this hard-to-treat population

NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): From clinical trials to clinical practice

Background: Pancreatic adenocarcinoma is an aggressive disease with poor prognosis. In a randomized phase III trial, combination of Nab-paclitaxel (Nab-P) plus gemcitabine showed superior activity and efficacy in first-line treatment compared with gemcitabine alone. Methods: Nab-P is not dispensed in Italy; however, we obtained this drug from our Ethics Committee for compassionate use. The aim of this study was to evaluate the efficacy and safety profile of this Nab-P and gemcitabine combination in a cohort of patients treated outside clinical trials. From January 2012 to May 2014, we included 41 patients with advanced pancreatic adenocarcinoma receiving combination of 125 mg/m2 Nab-P and 1 g/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle, as first-line treatment. Median age of patients was 67 (range 41-77) years, and 11 patients were aged ≥70 years. Results: Eastern Co-operative Oncology Group performance status was 0 or 1 in 32 patients (78 %) and 2 in nine patients (22 %). Primary tumor was located in the pancreatic head or body/tail in 24 (58.5 %) and 17 (41.5 %) patients, respectively, and nine patients had received biliary stent implantation before starting chemotherapy. Median carbohydrate antigen 19-9 level was 469 U/l (range 17.4-61546 U/l) and 29 patients (70.7 %) had referred pain at the time of diagnosis. Patients received a median six cycles (range 1-14) of treatment. Overall response rate was 36.6 %; median progression-free survival was 6.7 months [(95 % confidence interval (CI) 5.966-8.034), and median overall survival was 10 months (95 % CI 7.864-12.136). Treatment was well tolerated. No grade 4 toxicity was reported. Grade 3 toxicity included neutropenia in 10 patients (24.3 %), thrombocytopenia in five (12 %), anemia in three (7.3 %), diarrhea in four (9.7 %), nausea and vomiting in two (4.9 %), and fatigue in six (14.6 %). Finally, pain control was achieved in 24 of 29 patients (82.3 %) with a performance status improvement of 10 % according to the Karnofsky scale. Conclusions: Our results confirm that combination of gemcitabine plus Nab-P is effective both in terms of overall response rate, progression-free survival and overall survival, with a good safety profile

A possible connective tissue primary lymphoepithelioma-like carcinoma (LELC)

Lymphoepithelial carcinoma is an undifferentiated nasopharyngeal carcinoma with lymphoid stroma and non-keratinizing squamous cells with distinctive clinical, epidemiological and etiological features. Conversely, lymphoepithelioma-like carcinomas (LELCs) are carcinomas that arise outside the nasopharynx but resemble a lymphoepithelioma histologically. In this case study, LELC presentation in connective tissue (left sternocleidomastoid muscle) is peculiar and unusual, but its diagnosis is supported by histological findings and clinical history, especially long disease free survival and no primary lesions in nasopharynx and lung district. We also discuss the pathogenesis, hypothesizing an embryological theory. To our knowledge, it could be the first reported case of a primary connective tissue LELC to the neck

Prevention of regorafenib related skin toxicity in refractory metastatic colorectal cancer (mCRC) patients (pts): a single institution experience

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Serum thymidine kinase activity in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole: Results from the prospective BioItaLEE trial

Background: Thymidine kinase 1 (TK1) is an enzyme downstream of the CDK4/6 pathway, with a critical role in DNA synthesis; serum TK1 activity (sTKa) is a novel liquid biopsy biomarker of tumour cell proliferation. Methods: The phase IIIb, BioItaLEE trial (NCT03439046) collected sera from postmenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) treated with first-line ribociclib plus letrozole at baseline, day 15 of cycle 1 (C1D15), day 1 of cycle 2 (C2D1), and at first imaging. Associations between sTKa assessed at different time points or sTKa dynamic patterns, and progression-free survival (PFS) were evaluated using multivariate Cox models. Results: Overall, 287 patients were enroled. Median follow-up was 26.9 months. High sTKa (>median) at baseline was associated with higher risk of progression (hazard ratio [HR], 2.21; 95% confidence interval [95% CI], 1.45, 3.37; P = 0.0002); similar results were observed for patients with high sTKa levels at C1D15 and C2D1. Early sTKa dynamic patterns were strongly predictive of PFS. The pattern with high sTKa levels at C2D1 following initial decrease at C1D15 was associated with higher risk of progression versus the pattern with low sTKa levels at both time points (HR, 2.89; 95% CI, 1.57, 5.31; P = 0.0006), while the pattern with high sTKa levels at C1D15 was associated with the shortest PFS (HR, 5.65; CI: 2.84, 11.2; P < 0.0001). Baseline and dynamic sTKa changes provided independent information. Conclusions: sTKa appears to be a new promising prognostic and pharmacodynamic biomarker in patients with HR+/HER2– ABC treated with ribociclib plus letrozole as first-line therapy

lba14_prthe hoboe 2 multicenter randomized phase iii trial in premenopausal patients with hormone receptor positive early breast cancer comparing triptorelin plus either tamoxifen or letrozole or letrozole zoledronic acid

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